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EVALUATION OF MUSCLE-DIRECTED SKL OVEREXPRESSION IN SOD1<SUP>G93A</SUP> ALS MICE AND CHARACTERISATION OF PFN1<SUP>G118V</SUP> AS A SECOND MODEL FOR ALS STUDIES
Judith Sauledaand 7 co-authors
Institut de Neurociències, Universitat Autònoma de Barcelona
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS06-09PM-057
Presentation
Date TBA
Board: PS06-09PM-057
Event Information
Poster Board
PS06-09PM-057
Poster
View posterAbstract
Amyotrophic Lateral Sclerosis (ALS) is a heterogeneous neurodegenerative disorder characterized by progressive loss of both upper and lower motor neurons (MNs). Due to its complexity, no treatments for most ALS patients are available. α-Klotho (KL) is a pleiotropic protein with neuroprotective and muscle-regenerative properties. We evaluated a gene therapy approach driving muscle-specific overexpression of secreted Klotho (sKL) using myotropic adeno-associated viral vectors (MyoAAV) in the SOD1G93A mice. MyoAAV-driven sKL overexpression protected neuromuscular junctions (NMJs) from degeneration and preserved the MN located in the ventral horn of the spinal cord. This protection translated into a preserved neuromuscular function of both lower motoneurons and of the corticospinal tracts in treated SOD1G93A mice. Moreover, sKL overexpression enhanced motor performance and importantly, extended survival in the treated animals. To further investigate the beneficial effects of sKL as a potential treatment for ALS, a second mouse model overexpressing the human mutant form of PFN1G118V gene was characterized. PFN1G118V mice exhibited a progressive reduction in compound muscle action potential (CMAP) amplitude in the tibialis anterior, beginning before disease onset. This was preceded by decreased motor evoked potential (MEP) amplitudes, indicating early dysfunction of corticospinal tracts. Consistently, rotarod testing revealed progressive motor deficits over time. Thus, this model exhibits ALS pathogenic phenotypes, making it suitable for our future sKL-based gene therapy strategies.
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